Inactivating Mutations of Luteinizing Hormone β-Subunit or Luteinizing Hormone Receptor Cause Oligo-Amenorrhea and Infertility in Women

Abstract

Women harbouring inactivating mutations in luteinizing hormone (LH) beta subunit (LHB) or LH receptor (LHCGR) genes have similar clinical manifestations characterized by female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligo-amenorrhea and infertility. Oestradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels, confirming lack of ovulation. Notably, serum LH levels are low in patients with LHB mutations and high in those with LHCGR mutations, whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. Women with LHB mutations may be treated with hCG (human chorionic gonadotropin) or LH, whereas those with mutations in LHCGR are resistant. Lhb and Lhcgr knockout female mice are close phenocopies of the respective human mutations, and confirm that early follicular development, low levels of oestrogen production and theca cell development are independent of LH action, which is necessary for ovulation. Although inactivating mutations in LHB and LHCGR are rare in comparison to other genetic and non-genetic causes of hypogonadism, they should be considered in the differential diagnosis of oligo-amenorrhea and infertility.

Structure, function and regulation of gonadotropin receptors – A perspective

“…Single amino acid substitution leading to inactivating mutations of LHR have been reported to cause loss of leydig cell function (Laue et al, 1995) and pseudohermaphroditism (Qiao et al, 2009), hypospadias and micropenis in homozygous or compound heterozygous 46XY individuals (Latronico and Segaloff, 1999; Qiao et al, 2009; Themmen and Huhtaniemi, 2000). Inactivating mutations of the LH receptor have been reported in women with oligo-amenorrhea and infertility (Arnhold et al, 2009; Latronico and Segaloff, 1999; Themmen and Huhtaniemi, 2000). Recently, a missense mutation of LHR with impaired hCG responsiveness has been implicated for the empty follicle syndrome (Yariz et al, 2011).…”

Genetics of Premature Ovarian Failure

“…LH receptors mutations conclude with oligoamenorrhea, secondary amonerrhea or infertility mostly. LH levels are higher, FSH levels are normal/slightly higher and estradiol levels are compatible with midfollicular phase, there are antral follicles in overs but there is no ovulation (34). BRCA1 mutations have been indicated to be related with infertility and poor response to ovarian stimulation recently.…”

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

“…These patients have typical external genital organs, albeit sometimes highly hypotrophic. Indeed, masculinization of the urogenital sinus depends on testosterone secretion secondary to fetal Leydig cell stimulation by placental human chorionic gonadotropin (hCG) (19), an extrapituitary gonadotropin that is secreted normally during gestation in such cases.…”